Abstract A reduction in disease severity is the most likely indicator that an RSV vaccine is effective in young infants, the highest priority target population. However, we don't have precise markers to objectively assess RSV disease severity, which has made the evaluation of RSV vaccines in infants challenging. By applying a systems immunology approach our goal is to define the immune profiles, serum antibody responses, and RSV NS variants in infants with mild RSV infection, who represent the ideal model of a desirable vaccine induced outcomes. Based on our preliminary data we hypothesize that robust interferon (IFN) and innate immune responses, related in part to viral NS1 and/or NS2 variants, result in optimal B-cell activation, antibody responses (measured in Core C), and improved clinical outcomes in RSV infected infants. Identification of the ?safe and protective? profile to natural RSV infection will inform the selection of vaccine candidates (develop in Projects 1,2,3) in cotton rats (Core B) that should induce similar (or improved) profiles. In addition, these prototype profiles will serve as surrogate markers for the ?safe and protective? response in future vaccine trials testing the live attenuated RSV vaccine developed in this P01. We will test our hypothesis with the following specific aims: 1) Define the blood transcriptional signatures that correlate with mild RSV infection; 2) Define quantity and neutralizing activity of specific RSV antibodies associated with acute and long-term protection from severe RSV infection; 3) Identify the RSV NS1 and NS2 gene haplotypes that best correlate with disease severity.